tbuckley/cabot-search huggingface dataset:
Abstract 2645: A high-throughput platform for targets screening by membrane protein library
Authors: dan Li, Junyi Xiong, Jinying Ning, Feng Hao
Journal: Cancer Research (2023)

Abstract The specificity of antibodies, CAR-T cells and other biologic therapeutics to their binding targets is important to evaluate drug quality. The non-specific binding may lead serious toxic side effects. Therefore, specificity detection is an important step in the evaluation process of drug development. At present, the non-specific binding of antibody drugs is often verified only after serious adverse reactions founding in clinical trials, which may result in drug safety accidents and the abandonment of previous studies. To address the need for antibody target deconvolution and receptor identification, we developed a novel approach “AB5000”. AB5000 is an excellent solution for antibody specificity screening which enable early off-target screening and can de-risk the antibody drug development program. The AB5000 makes use of the full coverage membrane protein, representing over 5465 unique human membrane proteins including receptors, transporters, enzymes, miscellaneous and other membrane protein. Gene vector was transfected into target cells. Each membrane protein introduces a C-terminal epitope tag, allowing confirmation of protein expression and cellular location. To provide the highest level of sensitivity, we use luciferase reporter cell line system which is more rapid, simple and highly sensitive than flow cytometry or other binding assays. The AB5000 has widely application in testing the specificity of antibodies, deconvolution of orphan antibodies and ligands, detection of CAR-T proteins. The AB5000 represents a rapid, comprehensive, and highly sensitive platform for identifying the membrane protein targets of a wide variety of antibodies, protein ligands, and functional interactions. It is a promising powerful tool for biotherapeutic modalities development. Citation Format: dan Li, Junyi Xiong, Jinying Ning, Feng Hao. A high-throughput platform for targets screening by membrane protein library [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2645.
Abstract 1317: Exercise training prevents exosome mediated pre-metastatic niche formation in the liver
Authors: Ruiqi Yang, Tony Haykal, Celine Tohme, Ronghua Wang, Christof Kaltenmeier, David Geller, Hamza Yazdani, Samer Tohme
Journal: Cancer Research (2023)

Abstract Introduction: Primary tumor cells release exosomes facilitating pre-metastatic niche formation in distant organs, initiating the process of metastasis. As metastasis is the main prognostic factor for patients, it is essential to understand the pre-metastatic niches and develop therapies to target them. It has been shown that Kupffer cells play an crucial role in the formation of pre-metastatic niche in the liver. We have recently shown that exercise training (ExT) alters the phenotype of Kupffer cells and attenuates tumor metastasis after surgery. Here, we hypothesize that ExT can interfere with exosome mediated pre-metastatic niches, hence decreasing metastasis. Methods: Eight-week-old male mice were randomized into sedentary and ExT group. Mice were pre-educated with cancer exosomes for 4 weeks to induce pre-metastatic niche and intra-splenically injected with murine colorectal cancer (MC38) cells. Tumor metastasis and growth was followed by 3 weeks. Results: Compared to the sedentary group, there was a significant decrease in metastatic nodules and hepatic tumor replacement in the ExT mice liver. To further study the effects of ExT, livers from both groups were harvested 4 weeks after exosome pre-education. We observed decrease in the uptake of tumor exosome, immune cells infiltration and fibronectin deposition in the ExT livers, which demonstrates less pre-metastatic niche formation. Bulk RNA sequencing was performed on Kupffer cells isolated from both groups. Ingenuity pathway analysis shows that Triggering Receptor Expressed on Myeloid cells 1 (TREM1) signaling pathway was downregulated in EXT group, indicating less activation of Kupffer cells. Conclusions: These results indicate that exercise reduces pre-metastatic niche formation and tumor metastasis by affecting the interaction between cancer exosomes and Kupffer cells. In light of these findings, potential may exist to reduce exosome-induced liver pre-metastatic niches through the use of ExT as a nonpharmacologic therapy in patients with cancer. Citation Format: Ruiqi Yang, Tony Haykal, Celine Tohme, Ronghua Wang, Christof Kaltenmeier, David Geller, Hamza Yazdani, Samer Tohme. Exercise training prevents exosome mediated pre-metastatic niche formation in the liver [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1317.
Abstract 139: Exploiting interactions between ploidy and host physiology
Authors: Noemi Andor
Journal: Cancer Research (2023)

Abstract Whole-genome doubling facilitates rapid tumor evolution and is a hallmark of many cancers, including Glioblastoma (GBM) where it has an incidence of ~14%. GBM remains uniformly lethal, with a median overall survival of 14-16 months, despite aggressive therapy. In people aged 65 and above, prognosis is even more dismal, with median survival of less than 7 months. While comorbidities explain some of the increased age-related risk, age-related changes in the tumor microenvironment likely also contribute. Aging brains have higher incidence of polyploidy (Pearson r=0.80; P=0.031; Nandakumar et al., 2021), hypoxia related gene expression (Pearson r =0.22, P =0.008) and Glucose levels (Ding et al., 2021) as well as decreased stiffness (Hiscox et al., 2018). The average ploidy of 20 different cancer types correlates with the Oxygen levels recorded in their respective tissue of origin (Spearman r = 0.66, P = 0.002). Together these results suggest that availability of metabolic substrates in the GBM environment drives different cell fate decisions in cancer cells of different ploidy and shapes GBM disease initiation. We address this hypothesis with integrated in-vitro and in-silico experiments and multi-omic and imaging analysis of primary and recurrent GBM. We genetically engineered cell lines to obtain diploid and tetraploid lineages for each and tested how exposure to variable gradients of glucose, hypoxia and phosphate affect their migratory patterns. We performed RNA-seq and WGS of multiple regions obtained from two patient-matched primary and recurrent GBM. Pre- and post-surgery MRI data was available from both surgeries and registered to a T1 map Atlas to quantify stiffness and oxygenation in the brain. This data was used to calibrate a Stochastic State-Space Model (S3MB) we developed to recapitulate re-growth of enhancing primary tumor margins into the respective recurrent tumor. The model domain is initiated from MRI data and consists of 4mm3 voxels. Each voxel state is defined by 8+ variables that are updated over time: Stiffness, Oxygen, Phosphate, Glucose, Vasculature, Dead cells, migrating cells and proliferating cells of various ploidies. In-vitro results, multi-omics results and similarity between observed and simulated recurrent tumors were used to infer model parameters (resource consumption-, migration-, death and proliferation rates). Running the model backwards in time, we predict the local point of origin (LPO) of each GBM. We found that resource availability in the predicted LPO was correlated to WGD status, suggesting conditions in the local environment in which a GBM originates shape the outcome of an early competition between diploid and tetraploid cells. Citation Format: Noemi Andor. Exploiting interactions between ploidy and host physiology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 139.
Abstract 6258: The discovery and preclinical characterization of the potent covalent KRASG12C inhibitor UCT-001024
Authors: Tristin E. Rose, Brendan M. O'Boyle, Justin A. Hilf, Emma L. Baker-Tripp, Zhengao Feng, Kevin Yang, Michael D. Bartberger, Oliver C. Losón, Neil A. O'Brien, Martina S. McDermott, Naeimeh Kamranpour, Weiping Jia, Tong Luo, Raul Ayala, John Glasby, Brian M. Stoltz, Dennis J. Slamon
Journal: Cancer Research (2023)

Abstract Small molecule inhibitors of KRASG12C have garnered substantial interest as a targeted therapy for lung, colon and pancreatic cancers bearing this mutation. Data from multiple clinical programs have shown strong efficacy in lung tumors but diminished and differential efficacy for other tumor sites including lung-derived brain metastases. We undertook a series of in vitro and in vivo studies to evaluate clinically staged KRASG12C inhibitors in an effort to elucidate pharmacological factors underlying these clinical differences and identified potency, permeability/efflux, and clearance as impediments to efficacy, particularly in the context of brain metastases. Adagrasib is reportedly efficacious in patients with brain metastases. Our preclinical experimentation suggests that distinguished potency and pharmacokinetics are critical to therapeutic benefit, particularly in the context of brain metastases. Using both structure- and ligand-based design approaches, we identified a development candidate UCT-001024, which is a covalent KRASG12C inhibitor that demonstrates superior target-engagement kinetics and cellular potency in vitro. UCT-001024 also demonstrates improved plasma and whole brain unbound clearance, and in vivo potency in ectopic xenograft models and a brain-tropic NSCLC metastasis model relative to adagrasib. Additionally, UCT-001024 shows a favorable DDI profile and ion channel safety in an in vitro iPSC-derived cardiomyocyte cardiac proarrhythmia assay. Citation Format: Tristin E. Rose, Brendan M. O'Boyle, Justin A. Hilf, Emma L. Baker-Tripp, Zhengao Feng, Kevin Yang, Michael D. Bartberger, Oliver C. Losón, Neil A. O'Brien, Martina S. McDermott, Naeimeh Kamranpour, Weiping Jia, Tong Luo, Raul Ayala, John Glasby, Brian M. Stoltz, Dennis J. Slamon. The discovery and preclinical characterization of the potent covalent KRASG12C inhibitor UCT-001024 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6258.
Abstract 1573: Inhibition of acetyl-CoA carboxylase induced spindle abnormalities
Authors: Chieh-Ting Fang, Hsiao-Hui Kuo, Sih-Long Liu, Jhong-Syuan Yao, Ling-Huei Yih
Journal: Cancer Research (2023)

Abstract Acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in the de novo fatty acid synthesis pathway, is required for successful cell division in yeast, indicating that fatty acid synthesis may be regulated in order to properly safeguard nuclear and cell division. ACC is also phosphorylated during mitosis and this inhibitory phospho-ACC is accumulated at the spindle pole at metaphases. In this study, we set out to understand the role of ACC in the regulation of mitotic spindle assembly in human cells. We found that inhibition of ACC with TOFA induced spindle defects and cell death. The spindle defects induced by TOFA could be rescued by exogenous palmitic acid (PA), the immediate products of fatty acid synthesis. Inhibiting protein palmitoylating or depalmitoylating enzymes could induced spindle defects. These data indicate that well-regulated cellular PA levels and protein palmitoylation are required to assure accurate spindle assembly. In addition, the spindle microtubules comprised of α-tubulins mutated at the reported palmitoylation site exhibited disrupted dynamic instability. These results reveal that ACC may modulate tubulin palmitoylation during mitosis to delicately control MT dynamic instability and spindle assembly, thereby safeguarding nuclear and cell division. Citation Format: Chieh-Ting Fang, Hsiao-Hui Kuo, Sih-Long Liu, Jhong-Syuan Yao, Ling-Huei Yih. Inhibition of acetyl-CoA carboxylase induced spindle abnormalities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1573.
Abstract 5269: RF-1302, a novel dual inhibitor of PIM1 and FLT3 in preclinical treatment of acute myeloid leukemia
Authors: Weiwei Qi, Yanjun Zhang, Lei Zhao, Ailian Zhang, Chunze Zhang, Xiaoming Zhang, Lijuan Li, Huaquan Wang, Zonghong Shao, Rong Fu
Journal: Cancer Research (2023)

Abstract It was reported that PIM (Proviral Insertion site in Moloney murine leukemia virus) proteins are family kinases (PIM1, PIM2, and PIM3), which are upregulated in several cancer types, especially PIM1 is highly expressed in hematopoietic malignancies. PIM kinase family are responsible for enhancement of cell cycle, inhibition of apoptosis, activation of transcription, and cell homing/migration. Fms-like tyrosine kinase 3 (FLT3) is part of a family of receptor tyrosine kinases (RTKs), and a molecular therapeutic target of acute myeloid leukemia (AML). There are three FTL3 inhibitors, midostaurin, gilteritinib, and quizartinib have been approved for clinical treatment of AML. We have developed a novel dual inhibitor of PIM1 and FLT3, RF-1302 and evaluated its inhibition of cell proliferation in vitro and antitumor activity in vivo. RF1302 was found to have a strong inhibitory activity against target enzymes (PIM1 IC50 at 1.0-2.3 nM and FLT3 IC50 at 0.8-2.2 nM), which were more potent than the tested positive control drugs gilteritinib, quizartinib, and midostaurin. RF-1302 showed to be highly cytotoxic to cultured human acute myeloid leukemia (AML) cells (MV4-11 and Molm-13) with IC50 at 5.7nM and 9.5 nM, respectively. The in vivo antitumor activity of RF-1302 was evaluated and compared with midostaurin and gilteritinib in the treatment of the two AML xenograft models. RF-1302 at 20 mg/kg/daily x 14, oral) significantly delayed tumor growth and resulted in a tumor growth inhibition (TGI) of 95% (p&amp;lt;0.001 compared with the control group) in the Molm-13 AML model, and cured all of the tumor-bearing mice in the MV4-11 AML model. The antitumor activity of RF-1302 was superior to gilteritinib (TGI=46-55%) and midostaurin (TGI=63-75%). The treatment with RF-1302 showed very little toxicity (only 2% body weight loss) which were well below the maximum tolerated dose. These preclinical results suggest that RF-1302 represents a novel dual inhibitor of PIM1 and FLT3, which may constitute a highly efficacious modality for the treatment of FLT3 mutant AML, and is worthy of further clinical evaluation. Citation Format: Weiwei Qi, Yanjun Zhang, Lei Zhao, Ailian Zhang, Chunze Zhang, Xiaoming Zhang, Lijuan Li, Huaquan Wang, Zonghong Shao, Rong Fu. RF-1302, a novel dual inhibitor of PIM1 and FLT3 in preclinical treatment of acute myeloid leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5269.
Abstract 3814: In CLL the U1 snRNA driver mutation alters splicing in multiple genes and pathways
Authors: Andrea Senff-Ribeiro, Fatemeh Almodaresi, Quang Trinh, Shimin Shuai, David Spaner, Xose S. Puente, Elias Campo, Lincoln D. Stein
Journal: Cancer Research (2023)

Abstract 5-10% of patients with the IGHV wild type form of chronic lymphocytic leukemia (CLL) carry a g.3A&amp;gt;C driver mutation in the U1 small nuclear RNA (snRNA). We investigatedthe patterns of mis-splicing and their pathway consequences in three U1-mutant CLL cellline models using long read sequencing in order to better understand the mechanisms ofoncogenicity in tumors carrying this mutation. CLL cell lines (HG3, JVM3 and MEC1) expressing the U1 mutation and their wild-type counterparts were submitted to Oxford Nanopore sequencing to generate full-length RNA transcripts. This transcriptomic datawas evaluated, together with previously obtained short-read data. The g.3A&amp;gt;C mutation occurs at a specific location of the U1 snRNA, a core component of the eukaryotic spliceosome, and acts by altering the 5' splice site (5'SS) recognition sequence to cause consistent patterns of mis-splicing. Long read analysis identified multiple instances of intron retention and suppression of exon skipping, and in silico translation of these mis-splicing events predicted stop-gain and other loss of function mutations in several expressed genes, as well as widespread changes in gene expression levels. We performed a pathway overrepresentation analysis of the altered gene expression patterns in the mutant cells using the Reactome knowledgebase and identified an enrichment in the processes of translation, non-sense mediated decay (NMD) and immune signaling, including interferon signaling. In particular, there was a marked down-regulation of genes related to ribosomal assembly and the translational machinery. A more comprehensiveanalysis of the U1 mutation phenotype in CLL may accelerate the development ofbetter therapeutic and diagnostic approaches in patients. Citation Format: Andrea Senff-Ribeiro, Fatemeh Almodaresi, Quang Trinh, Shimin Shuai, David Spaner, Xose S. Puente, Elias Campo, Lincoln D. Stein. In CLL the U1 snRNA driver mutation alters splicing in multiple genes and pathways. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3814.
Abstract 5030: Treatment of aromatase inhibitor-resistant cells with polyisoprenylated cysteinyl amide inhibitors stimulates the mitogen-activated protein kinase pathway enzymes, impedes cell proliferation and causes cell death
Authors: Jassy Mary S. Lazarte, Syreeta L. Tilghman, Nazarius S. Lamango
Journal: Cancer Research (2023)

Abstract Overexpression and hyperactivity of the estrogen receptor drives 67-80% and 90% of breast cancer in women and men, respectively. Resistance to aromatase inhibitor (AI) therapies necessitates the continuous search for novel therapies. Previous studies demonstrate AI-resistance is associated with hormone-independence, enhanced motility, and increased growth factor signaling. Here, long-term letrozole-treated (LTLT-Ca) breast cancer cells were used to evaluate polyisoprenylated cysteinyl amide inhibitors (PCAIs) as potential alternative therapies for the treatment of aromatase inhibitor-resistant breast cancer. We determined the potency of PCAIs as anticancer agents by evaluating their effects on cell viability, phosphorylation of MAPK pathway enzymes, G-proteins levels, cell migration and apoptosis. Among the PCAIs tested, NSL-YHJ-2-27 showed significant potency against cell viability with an EC50 of 3.6 µM. MEK (p-MEK1/2), ERK (p-ERK1/2), and p90RSK (p-p90RSK) phosphorylation were significantly increased by 178, 119 and 125%, respectively, over controls. In addition, of the seven G-proteins evaluated, only KRAS and NRAS showed significant increases of 49% and 97%, respectively. Cell proliferation and colony formation were impeded by 82% and 74%, respectively, after PCAIs treatment. Migration of the LTLT-Ca cells was inhibited by 80% following treatment with 5 µM of NSL-YHJ-2-27. Lastly, the PCAIs also caused the degeneration of the spheroids after 10 µM PCAIs treatment, dead cells were very apparent after AO/EB staining. Our findings suggest that the PCAIs’ suppression of cell viability and activation of the MAPK pathway causes apoptosis possibly through the activation of the proapoptotic p-p90RSK isoforms. The results reveal the ability of the PCAIs to effectively cause a negative impact on several cancer hallmarks suggesting their potency as anticancer agents. These findings also support a potential role for PCAIs’ use in treating breast cancers that have become resistant to aromatase inhibitor therapies. Citation Format: Jassy Mary S. Lazarte, Syreeta L. Tilghman, Nazarius S. Lamango. Treatment of aromatase inhibitor-resistant cells with polyisoprenylated cysteinyl amide inhibitors stimulates the mitogen-activated protein kinase pathway enzymes, impedes cell proliferation and causes cell death. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5030.
Abstract 4468: Tumor-derived extracellular vesicles transmit retroelement and pericentromeric RNAs to drive proinflammatory and DNA damage responses in stromal fibroblasts and immune cells
Authors: Valentina Evdokimova, Peter Ruzanov, Hendrik Gassmann, Lincoln D. Stein, Poul H. Sorensen, Stefan Burdach, Laszlo Radvanyi
Journal: Cancer Research (2023)

Abstract Chronic cancer-associated inflammation and immunosuppression are common features in most patients with solid malignancies. The causes of this chronic inflammatory-immunosuppressive state are still largely undefined. We hypothesized that selective RNAs can be secreted by cancer cells in extracellular vesicles (EVs) and may trigger proinflammatory responses in target cells, leading to chronic inflammation linked to immune cell dysfunction and immunosuppression. We found that tumor cell lines from pancreatic ductal adenocarcinoma (PDAC), prostate cancer (PCa) and from pediatric cancer such as Ewing sarcoma (EwS) continuously secrete large numbers of small (40-200 nm) EVs. In contrast to non-transformed fibroblasts, cancer cell-derived EVs are enriched with large subsets of retroelement and pericentromeric transcripts, including LINE, SINE and HERV retroelements, and human satellite 2 and 3 (HSAT2,3) RNAs. These virus-like RNAs were highly elevated in plasma EVs from EwS patients but not in healthy donors. Some of them, including HERV-K and HSAT2, were detected in peripheral blood myeloid cells with CD33+HLA-DR− immunosuppressive phenotypes, and these cell populations were expanded in EwS patients compared to healthy donors. Using mouse xenografts and in vitro models, we also found that at least some of these RNAs, such as HSAT2, are transmitted to stromal fibroblasts and immune cells in the tumor microenvironment. They also accumulated in fibroblasts after treatment with EwS EVs, coincident with the induction of proinflammatory and DNA damage responses. Prolonged exposure of fibroblasts to EwS EVs also led to mitotic defects and senescence. Expression and dissemination of these highly immunogenic virus-like RNAs in EVs may thus be a common feature of multiple human malignancies, potentially affecting host cells in the local and systemic tumor environment. This, in turn, may induce chronic inflammation contributing to an overall immunosuppressed state in patients. Citation Format: Valentina Evdokimova, Peter Ruzanov, Hendrik Gassmann, Lincoln D. Stein, Poul H. Sorensen, Stefan Burdach, Laszlo Radvanyi. Tumor-derived extracellular vesicles transmit retroelement and pericentromeric RNAs to drive proinflammatory and DNA damage responses in stromal fibroblasts and immune cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4468.